tbuckley/cabot-search huggingface dataset:
DDEL-13. ULTRASOUND-ENHANCED DELIVERY OF LIPOSOMAL DOXORUBICIN ACROSS THE BLOOD BRAIN BARRIER INDUCES AN IFN-GPHENOTYPE IN MICROGLIA, MACROPHAGES, AND T CELLS AND IMPROVES RESPONSE TO PD-1 BLOCKADE IN GLIOMAS
Authors: Victor Arrieta, Andrew Gould, Kwang Soo Kim, Crismita Dmello, Daniel Zhang, Brandyn Castro, Li Chen, Surya Pandey, Li Kai, Joseph Duffy, Matthew McCord, Rachel Ward, Miguel Muzzio, Michael Canney, Irina Balyasnikova, Bin Zhang, Craig Horbinski, Jason Miska, Roger Stupp, Catalina Lee-Chang, Adam M Sonabend
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Given the limited drug penetration across the blood-brain barrier (BBB), the therapeutic potential of new and existing therapies has not been fully exploited for the benefit of glioblastoma (GBM) patients. METHODS Here we employed a novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) that temporarily opens the BBB to deliver liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in mouse glioma models and 3 recurrent GBM patients. Immunological variables were evaluated in tumor and immune cells as well as efficacy in glioma-bearing mice treated with DOX delivered by LIPU. These included measurement of HLA ABC and HLA DR protein expression by tumor cells, microglia, and macrophages and IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors. We also assessed efficacy of LIPU/MB enhanced combination therapy in glioma-bearing mice. RESULTS Upregulation of HLA ABC and HLA DR was observed in GBM cell lines at low concentrations of DOX. Tumor cells from GBM patients treated with DOX, aPD-1 and LIPU/MB showed increased expression of HLA ABC and HLA DR compared to paired pretreatment samples. In both mice and humans, LIPU/MB liposomal DOX increased absolute brain drug concentrations and elicited a specific IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans. Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice and in peritumoral regions of GBM patients. Combined treatment with liposomal DOX and aPD-1 delivered with LIPU/MB resulted in long-term survival of glioma-bearing mice that relied on the activity of CD8+ T cells for its efficacy. CONCLUSIONS Overall, this translational study demonstrates the utility of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.
NIMG-24. LONGITUDINAL MR SPECTROSCOPY TO DETECT PROGRESSION IN PATIENTS WITH LOWER-GRADE GLIOMA IN THE SURVEILLANCE PHASE
Authors: Lauro Avalos, Tracy Luks, Tyler Gleason, Pablo Damasceno, Yan Li, Janine Lupo, Joanna J Phillips, Nancy Ann Oberheim Bush, Jennie Taylor, Susan M Chang, Javier Villanueva-Meyer
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Monitoring lower-grade gliomas (LrGGs) for disease progression is made difficult by the limits of anatomical MRI to distinguish treatment-related tissue changes from tumor progression. MR spectroscopic imaging (MRSI) offers additional metabolic information that can help address these challenges. The goal of this study was to compare longitudinal changes in multiparametric MRI, including diffusion-weighted imaging, perfusion imaging, and 3D MRSI, for LrGG patients who progressed at the final time point and those who remained clinically stable. METHODS Forty-one patients with LrGG who were clinically stable were longitudinally assessed for progression. Changes in anatomical, diffusion, perfusion, and MRSI data were acquired and compared between patients who remained clinically stable and those who progressed. RESULTS Thirty-one patients remained stable, and 10 patients progressed. Over the study period, progressed patients had a significantly greater increase in normalized choline, choline-to-N-acetylaspartic acid index (CNI), normalized creatine, and creatine-to-N-acetylaspartic acid index (CRNI), than stable patients. CRNI was significantly associated with progression status and WHO type. Progressed astrocytoma patients had greater increases in CRNI than stable astrocytoma patients. CONCLUSIONS LrGG patients in surveillance with tumors that progressed had significantly increasing choline and creatine metabolite signals on MRSI, with a trend of increasing T2 FLAIR volumes, compared to LrGG patients who remained stable. These data show that MRSI can be used in conjunction with anatomical imaging studies to gain a clearer picture of LrGG progression, especially in the setting of clinical ambiguity.
NIMG-99. REAL-TIME DELINEATION OF THE CENTRAL SULCUS WITH THE SPATIAL PROFILE OF SSEPS CAPTURED WITH HIGH-DENSITY ECOG GRID
Authors: Priscella Priscella, Sujit Prabhu, Shreyas Bhavsar, Tummala Sudhakar, Nuri Ince
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Cortical mapping during tumor resection is critical to reducing the risk of neurological complications. While the somatosensory evoked potential (SSEPs) is widely employed to delineate the central sulcus, the evoked response can be misconstrued from the manual peak interpretation. This is due to the poor spatial resolution of the strip electrode as well as a result of edema or tumor infiltration of the overlying cortex. We present a real-time computer-based visualization system that uses recorded SSEPs with a subdural grid to aid in cortical mapping. Method: The neural data during electrical stimulation of the median nerve at 0.6Hz are picked up with a bio-amplifier. The stimulation artifact recorded from the bipolar electromyogram (EMG) is used as the stimulation onset. The ECoG data are assessed online with MATLAB Simulink to process and visualize the SSEPs waveform. The visualization system is programmed to display the SSEP's peak activation as a heat map on a 2D grid and projected onto a screen, showcasing the nature of the cortical activities over the contact surface area in real-time. RESULTS SSEPs were recorded from 3 patients during their awake craniotomies. The ECoG grid occupied a large cortical surface where the heatmap delineated the central sulcus. The color-coding of the heatmap revealed the anterior and posterior channels, providing a consistently high separation accuracy in each patient (accuracy = 98%). The map could be viewed at any time point along the SSEP trace without peak interpretation. CONCLUSION We believe that this visualization system will aid in the rapid definition of the sensorimotor area during surgical planning to provide additional information during cortical mapping and facilitate interpreting ECoG grid data.
EXTH-55. DELIVERY OF CAS9/SGRNA RIBONUCLEOPROTEIN CONJUGATE VIA VIRUS-LIKE PARTICLES FOR EFFICIENT GENE EDITING OF TRANSCRIPTION FACTOR BRACHYURY IN GLIOBLASTOMA
Authors: Wesley Hsu, Baisong Lu, Yunping Hu
Journal: Neuro-Oncology (2022)

Abstract Brachyury, a transcription factor that is a critical driver during normal embryonic development, is highly expressed in glioblastoma (GBM) but rarely expressed in normal adult tissues. Recent evidence suggests that brachyury plays a crucial role in regulating GBM cell proliferation and stemness, implying the potential of brachyury as a therapeutic target. However, like other transcription factors, brachyury is not readily inhibited pharmacologically due to the absence of ligand-accessible small-molecule binding pockets, and a direct inhibitor of brachyury has not been identified. Our team has recently developed a novel virus-like particle (VLP)-based system by fusing aptamer-binding protein to the lentiviral nucleocapsid protein within the group-specific antigen, which allows for efﬁcient packaging of Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) for gene editing. Our data suggests that our VLP-mediated Cas9/gRNA RNP allows for transient expression of Cas9 in patient-derived GBM cells while maintaining effective gene editing efficiency (∼40%). Our strategy results in 90% knockdown of brachyury in vitro with subsequent inhibition of GBM cell proliferation and stemness as well as enhanced susceptibility of tumor cells to radiation via increased cleavage of caspase-3. In addition, our in vivo results using a xenograft mouse model further demonstrates that transduction with VLP-packaged Cas9/brachyury gRNA inhibits GBM progression. Our findings demonstrate that our novel VLP-based system allows for efficient delivery of Cas9/gRNA RNP-based brachyury gene editing technology and represents a novel treatment strategy for GBM.
CTNI-68. FIREFLY-1 (PNOC026): PHASE 2 STUDY OF PAN-RAF INHIBITOR TOVORAFENIB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RAF-ALTERED RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA OR ADVANCED SOLID TUMORS
Authors: Lindsay Kilburn, Daniel Landi, Sarah Leary, David Ziegler, Patricia Baxter, Andrea Franson, Geoffrey McCowage, Angela Waanders, Jasper Van der Lugt, Michal Yalon Oren, Nicolas Gerber, Nicholas Gottardo, Dong-Anh Khuong-Quang, Karsten Nysom, Simon Bailey, Pablo Hernáiz Driever, Sebastien Perreault, Olaf Witt, Seungmin Hahn, Darren Hargrave, Timothy Hassall, Nada Jabado, Hyoung Jin Kang, Valerie Larouche, Helen Toledano, Cassie Kline, Mohamed Abdelbaki, Susan Chi, Sharon Gardner, Nicholas Whipple, Sabine Mueller, Samuel Blackman, Xin Zhao, Daniel Da Costa, Michael Cox, Roger Packer, Jordan Hansford
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months–25 years who progressed following ≥ 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (≤ 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for ≥ 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review. RESULTS As of April 14, 2022, 25 patients were enrolled to arm 1 and had ≥ 6 months of follow-up. Median age at enrollment was 8 years (range 3–18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with ≥ 3 prior lines of therapy), and 72% previously received MAPK pathway-targeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade ≥ 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented. CONCLUSIONS Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG.
DDDR-03. DEVELOPMENT OF NOVEL ANTI-BRAIN METASTASIS INHIBITORS
Authors: Agata Kieliszek, Daniel Mobilio, Blessing Bassey-Archibong, Jarrod Johnson, Chitra Venugopal, Jakob Magolan, Sheila Singh
Journal: Neuro-Oncology (2022)

Abstract The current standard of care for (surgery and radiation) for brain metastases (BM) is inadequate as BM have a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need. The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Connectivity Map analysis was applied to the gene expression signatures of pre-metastatic BM cells to identity a compound (Drug A) which selectively inhibits BM cell proliferation but is not blood-brain barrier (BBB) penetrant and has not been previously considered in the context of brain metastasis. We synthesized a BBB-penetrant analogue of Drug A and found, using our patient-derived xenograft (PDX) models, that it increased survival benefit relative to both placebo and Drug A. Beginning with this promising scaffold, we will conduct structure-activity hypothesis-driven medicinal chemistry campaigns to optimize this scaffold for brain permeation while maintaining selective anti-BM activity. Development of novel small molecules that target premetastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.
CNSC-23. NEURONAL ORIGIN INFLUENCES SPONTANEOUS NETWORK ACTIVITY IN GLIOBLASTOMA-NEURON COCULTURES
Authors: Andy Daniel, Saritha Krishna, Galina Popova, Jasleen Kaur, Shawn L Hervey-Jumper
Journal: Neuro-Oncology (2022)

Abstract Neuronal activity is emerging as a driver of cancer initiation and proliferation. Several models have been developed to recapitulate cancer-neuron interactions within the tumor microenvironment; however, there is substantial diversity of neuronal subtypes within the murine and human cortex. Differences in the neuronal microenvironment may influence glioma cell behavior and fail to recapitulate in vivo mechanisms. Here, we investigate the electrophysiological properties of cortical neurons and activity-regulated paracrine signaling across co-culture conditions using microelectrode arrays (MEA). Cortical neurons were obtained from three conditions, (1) human prenatal tissues, (2) murine embyronic tissue (E18), and (3) murine postnatal tissue (P1.5), then co-cultured with primary patient-derived glioblastoma cultures. Neuronal activity was assessed using weighted mean firing rate (WMFR; spike rate multiplied by number of active electrodes) and network burst synchrony index. Characterization of the activity-dependent paracrine signaling was performed using proteomics. Initiation of spontaneous firing activity differed across neuronal conditions, with activity occurring earlier in postnatal P1.5 cultures (day in vitro [DIV] 7), whereas E18 and human prenatal cultures demonstrated delayed patterns of activity (DIV 14 and DIV 21, respectively). Glioblastoma cells were added on the first day of consistent spiking. All neuronal co-culture conditions demonstrated glioma-induced hyper-activity (increased WMFR), however in different patterns. E18 co-cultures exhibited glioma-induced hyperexcitability within 24 hours with a subsequent decrease in activity over 14 days with minimal synchrony. P1.5 demonstrated no glioma-induced hyper-excitability at 24 hours; however, WMFR peaked by 7 days and remained elevated through co-culture day 14 (including concurrent increase in synchrony). Human postnatal neurons demonstrated a steady and consistent increase in WMFR as early as 24 hours post co-culture and remained active through day 14 with no synchrony change. Our data suggest that careful consideration should go into selecting neuronal co-culture conditions for mechanistic studies.
EPCO-36. INVESTIGATING THE BAIAP2-CDC42 INTERACTION IN MEDULLOBLASTOMA
Authors: Luz Ruiz, Nitish Jangde, Nagi Ayad
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is the most common malignant brain tumor found in children. The standard of care is surgical removal, radiation, and chemotherapy. Despite advancements in treatment, there is still no significant improvement of survival rates using chemotherapy compared to no treatment. This indicates novel, more effective treatment options are necessary. In addition, there is a worst mortality rate when medulloblastoma is metastasized outside the central nervous system. Recent studies have identified that medulloblastoma tumors can disseminate via the bloodstream and cerebral spinal fluid. However, not much is known about the properties of metastasis and invasion in medulloblastoma. We set out to identify potential key regulators for the pathophysiology of medulloblastoma. I mined and analyzed Medulloblastoma patient tumor data along with data obtained from a 10X Genomics Chromium single-cell RNA sequencing experiment performed in the laboratory from a Tg (Neurod-Smoothened*A1) mouse to investigate cellular heterogeneity and identify potential regulators in the metastasis and invasion of medulloblastoma. We identified BAIAP2 and CDC42 to be differentially expressed in our data. Previous studies show that these genes are implicated in oncogenic properties, such as motility, filopodia, and invasion. We hypothesize that distinct cell populations within medulloblastoma should show different expressions of BAIAP2 and CDC42 and that there will be different expressions when compared to non-tumor brain cells. We determined that BAIAP2 and CDC42 have higher expression in medulloblastoma tumors compared to the control. Interestingly, BAIAP2 is enriched in the cell population for microtubule depolymerization. Moreover, we show the role BAIAP2 and CDC42 have in the invasion and metastasis of medulloblastoma. This study is important because BAIAP2 and CDC42 have yet to be characterized in medulloblastoma. We suggest that BAIAP2 and CDC42 have a role in the metastasis and invasion of medulloblastoma indicating it could be a possible target for future studies.
RADT-24. PHASE II STUDY OF PROTON RADIATION THERAPY FOR LOWER GRADE GLIOMAS
Authors: Jason Slater, Nora Horick, Lisa Nachtigall, Michael Parsons, Giuliana Zarrella, Nicholas Tritos, Jorg Dietrich, Jennifer Pursley, Barbara Fullerton, Irene Wang, Kevin Oh, Jay Loeffler, Beow Yeap, Helen Shih
Journal: Neuro-Oncology (2022)

Abstract PURPOSE To report preliminary results on outcomes of patients with lower grade gliomas (LGG) treated with proton therapy. METHODS Patients with grade II or IDH mutant grade III glioma and indications for radiation therapy were enrolled in a prospective single arm trial of proton therapy (PRT), receiving a dose of 54 Gy(RBE) or 59.4 Gy(RBE), respectively. Comprehensive baseline and regular post-treatment evaluations of neuroendocrine function, neurocognitive functions (NCF), quality of life (QOL), and progression-free survival (PFS) were performed. RESULTS Among 60 patients (median age 40.8) who received PRT, 28 (47%) were men, and 39 (65%) were WHO grade II. Eighteen patients (30%) were IDH mutant+1p/19q co-deleted, 36 (60%) were IDH mutant astrocytoma, and 6 (10%) were IDH wildtype. Treatment was at initial diagnosis (41; 68%) or progression (19; 32%). Median follow-up after PRT was 4.1 years. All current data are reported for 3 years from PRT. PFS at 3 years was 86% for all patients, 84% for grade II (n = 39), and 90% for favorable grade III gliomas (n = 21). PFS was 83% for IDH mutant astrocytoma, and 94% for IDH mutant+1p/19q co-deleted oligodendrogliomas. New endocrine dysfunction was detected in 3 patients (5%). There was one grade 4 case of brain necrosis (2%) but no grade 3 toxicities. NCF decline, defined by Z-score drop of &amp;gt;/= 1SD on clinical trials battery composite, occurred in 7% (n = 3/43). QOL assessment by FACT-Brain showed 16% with decline of &amp;gt;/= 10 points (n = 7/43). CONCLUSIONS At 3 years post-treatment, LGG patients receiving PRT have a high PFS, similarly to previous reports on photon therapy, few new neuroendocrine deficiencies, modest treatment toxicities, and minimal decline in NCF or QOL. These positive outcomes may be attributable to limited integral dose to the brain by use of PRT, demonstrating its value in treatment of LGG patients with long survival expectations.
EXTH-61. RPP25L IS A NOVEL DEPENDENCY IN GLIOBLASTOMAS WITH LOW RPP25 EXPRESSION
Authors: Elisa Aquilanti, Rebecca Chen, Keliana Hui, Lauren Kageler, John Prensner, Patrick Y Wen, Matthew Meyerson, Franklin Huang
Journal: Neuro-Oncology (2022)

Abstract Genetic redundancy is a property whereby two or more genes encode for the same biological function, and inactivation of one redundant gene has little effect on the overall phenotype. In recent years, genetic redundancy has been exploited as a cancer therapeutic strategy, as individual paralogs of essential genes are occasionally lost in cancers because of genomic deletions. Inactivation of the non-deleted paralog can therefore be selectively toxic to tumor cells. To identify cancer cells that may become reliant on the non-methylated paralog of essential genes, we performed an in-silico analysis of the correlation between DNA methylation and genetic dependency across large scale CRISPR knockout screens that revealed novel paralog dependencies. Through this analysis, we identified glioblastoma cell lines with hypermethylation of the RPP25 promoter and with sensitivity to loss of RPP25L. RPP25 is a known structural component of RNAse P, a key enzyme involved in tRNA maturation. While the biological function of RPP25L is unknown, it has significant sequence homology to RPP25. We used CRISPR editing and CRISPR interference to inactivate RPP25L in a panel of glioblastoma cell lines and demonstrated that cell lines that do not express RPP25 (SF295, GB1, LN18) exhibit a rapid reduction in viability upon RPP25L loss, whereas cell lines with retained RPP25 expression or re-expressed RPP25 are not affected. RPP25L dependency is associated with a marked reduction in nascent polypeptide formation as determined by click chemistry. Lastly, we validated RPP25L dependency in glioblastoma patient-derived neurospheres with loss of RPP25 expression. These results indicate that RPP25L is a promising novel therapeutic target in glioblastomas with hypermethylation of the RPP25 promoter.